The method of U.S. Pat. No. 4,708,955 and of published Japanese Kokai Koho No. 59-116291 (U.S. Pat. No. 4,496,562) (July 15, 1984) and corresponding U.S. Pat. No. 4,496,562 patented Jan. 29, 1983 involve synthesis of the acid of Formula I wherein R.sup.2, and R.sup.4 are H, and then esterification thereof with the desired physiologically hydrolyzable ester group, R.sup.4. This method is not suited for commercial scale development because chromatographic methods of purification are required and because the yield is low.
The present inventors have discovered that one reason for the low yield and purification difficulties in the foregoing esterification process is the formation of oximino O-substituted by-products, i.e. by-products wherein R.sup.2 is an acyl substituent. Thus the esterification of an oximino O-protected intermediate was conceived of, and an examination of the prior art was made to ascertain whether suitable intermediates were available. The referenced patent itself, U.S. Pat. No. 4,708,955, provides N,O-diprotected intermediates of Formula IV ##STR2## wherein R.sup.1 is 1-propenyl, R.sup.2 and R.sup.5 are respectively O- and N-protecting groups such as the trityl group, and R.sup.4 is a protective ester group such as diphenylmethyl. A further discovery of the present inventors is that removal of the R.sup.5 trityl group is not a facile reaction, and is another reason for the poor overall yield in the synthesis of prodrug esters of Formula I via intermediates of Formula IV. Selective removal thereof in the presence of the desired R.sup.4 physiologically hydrolyzable ester group was not therefore considered feasible in the present case, although analogous processes involving allegedly selective removal of R.sup.2 and R.sup.5 (Formula IV) protecting groups in the presence of an R.sup.4 ester group have been reported. Such is shown in published Japanese Kokai Koho No. 56-8391 (Jan. 28, 1981) and corresponding published British specification GB 2,051,066 published Jan. 14, 1981 with respect to the compound of Formula IV wherein R.sup.1 is methyl, R.sup.2 and R.sup.5 are trityl, and R.sup.4 is pivaloyloxymethyl, and in published Japanese Kokai Koho No. 59-65095 (Apr. 13, 1984) wherein R.sup.1 is --SCH.sub.3 or --SC.sub.2 H.sub.5, R.sup.2 and R.sup.5 are trityl, and R.sup.4 is pivaloyloxymethyl, or 1-ethoxycarbonyloxyethyl.
Another method used to prepare prodrug esters of Formula I wherein R.sup.2 and R.sup.3 are H, and R.sup.4 is a physiologically hydrolyzable ester group involves preparation of a 2-oximino-4-bromoacetoacetamido cephalosporin intermediate and conversion thereof to an aminothiazole by reaction with thiourea according to the following reaction scheme. ##STR3## The foregoing scheme is described in published Japanese Kokai Koho No. 59-89689 (May 23, 1984) and corresponding U.S. Pat. No. 4,559,334 patented Dec. 17, 1985.
Stepwise hydrolytic deprotection of a cephalosporin ester of Formula IV wherein R.sup.1 is the acetoxymethyl group, and R.sup.2, R.sup.4, and R.sup.5 are protective groups to yield the O-protected acid (Formula IV wherein R.sup.4 and R.sup.5 are H, R.sup.2 is trityl, and R.sup.1 is acetoxymethyl) has been described in U.S. Pat. Nos. 4,196,205 (Apr. 1, 1980), refer to Column 45, lines 25-33. Prodrug esters were not the subject of this patent, however, and no attempt to esterify the foregoing acid was described.
Acylation of the 7-amino group of the 3-substituted ceph-3-em-4-carboxylate of Formula II by compounds of Formula III herein R.sup.2 is methyl and AE is benzotriazol-1-yl is described in U.S. Pat. No. 4,714,760 (Brundige, et al. patented Dec. 22, 1987, column 9, line 4). The R.sup.2 methyl group is not regarded in the art as a protecting group since it is neither a readily introduced nor a readily removed group. ##STR4## No example exists in the prior art of using an acylation active ester of Formula III wherein R.sup.2 is a readily removable blocking group in cephalosporin antibiotic synthesis.
Bucourt, et al. have reported in Tetrahedron 34, 2233 (1978) that reaction of ethyl 2-(2-aminothiazol-4-yl)-2-hydroximinoacetate with one molecular proportion of trityl chloride in the presence of triethylamine yields selectively the N-trityl product. Two molecular proportions of trityl chloride yields the N,O-ditrityl product.